Virus World

The confusion came over labeling: The vaccine comes in vials labeled as containing enough for five doses, not the six they actually hold. With the Covid-19 vaccine in short supply, hospital pharmacists found themselves in the unexpected position of throwing away one in every six doses of the first Pfizer-BioNTech vaccines distributed this week in the United States. The confusion came over labeling: The vaccine comes in vials labeled as containing enough for five doses. But pharmacists discovered that, after thawing and mixing the contents with a dilutent, each vial contained enough vaccine for six doses. Without explicit approval from the manufacturer, that final dose had to be discarded. “It was overtly clear early on there’s some extra volume,” said Russell Findlay, pharmacy manager at University of Utah Health. His colleagues called Pfizer on Tuesday to ask if they could use the extra dose, said Findlay, but the company wouldn’t give a definitive answer.

Pharmacists and executives at several health care systems said they didn’t feel they could risk using the extra dose, especially as Pfizer’s vaccine requires two doses, 21 days apart, to be effective. “We’re not fully confident of our future supply. Let’s say we use the six but we get fewer doses in the future, we might not have enough for the second dose,” said Findlay. “We need to be very cautious in managing that supply.” Across the country in Boston, Paul Biddinger, medical director for emergency preparedness at Mass General Brigham, said he’d heard of the extra doses from the British vaccine rollout earlier this month. Despite being prepared, his team still had to throw out the additional doses on the first day of distribution.  In Texas, the extra doses were discarded on the first day of distribution but, by Wednesday morning, Houston Methodist Hospital chief executive Roberta Schwartz said her team heard from Pfizer that it was okay to use what’s in the vial. Finally, on Wednesday afternoon, the U.S. Food and Drug Administration updated its guidance, saying health care providers should feel free to use all the full doses within each vial. “At this time, given the public health emergency, FDA is advising that it is acceptable to use every full dose obtainable (the sixth, or possibly even a seventh) from each vial, pending resolution of the issue,” spokesperson Abigail Capobianco wrote in an email to STAT. But any spare half doses should not be combined with half doses from other vials to create a whole one, she added.

But Pfizer was less definitive. Each vial contains enough vaccine for at least five doses, spokesperson Sharon Castillo said in an email to STAT, and each dose must contain 0.3ml. “The amount of vaccine remaining in the multidose vial after removal of 5 doses can vary, depending on the type of needles and syringes used,” she wrote.  ”At this time, we cannot provide a recommendation on the use of the remaining amount of vaccine from each vial. Vaccinators need to consult their institution’s policies for the use of multidose vials.” If the dosing confusion was raised in the U.K., the FDA and Pfizer ideally should have issued clearer instructions about using the extra dose before distribution began this week in the U.S., said John Grabenstein, adviser to the American Pharmacists Association. “In a situation of limited supply, any waste is unfortunate.” But all injectable medicines have overfill, he said, and the first stages of clinical practice normally raise small issues. “There’s a thousand matters to address in the first week. This one might only now rise to the level of getting checked out,” he said. It makes sense to have some left-over liquid in a vial, said Findlay. Slight variations in the syringes used by different health systems could have small effects on the size of each dose, and changes in air pressure at different altitudes could also affect the volume of vaccine in a vial. Even with the confusion over dosing, the first day of administering vaccines was a success, he said: “Yesterday was the best day of work I’ve ever had.”

FDA Instructions to administer and prepare the vaccine: 

https://www.fda.gov/media/144413/download

AstraZeneca and the University of Oxford's coronavirus vaccine's high efficacy may have been in part due to a dosing error. In the press release on the vaccine's efficacy released on Monday, the vaccine candidate had a higher efficacy - up to 90% - in the group that received a half dose and then a full dose.  But the candidate vaccine was just 62% effective in the group that received two full doses. Mene Pangalos, head of biopharmaceuticals research and development at AstraZeneca, admitted to Reuters on Monday that some participants received a half dose and then a full dose due to a dosing error. Pangalos called it a "useful mistake" in a later interview with the New York Times, published on Wednesday. Oxford University said in a statement on Wednesday that some of the vials in the trial did not have the right concentration of vaccine. The university said the problem was discussed with regulators and they decided to complete the late-stage trial in two groups, according to the AP. 

Experts say the small number of people in the low dose group - some 2,741 - make it difficult to know if the effectiveness is a statistical quirk.  Also, none of the people in the low dose group were over 55 years old and younger people tend to have a stronger immune response than those who are older. A spokesperson for the University of Oxford told Euronews that "as a result of a difference in the manufacturing process" the phase I trial method was "shown to over-estimate the dose on the new batches of vaccine resulting in a half dose of the vaccine being administered as the first dose". After discussing with the regulator, the two different concentrations were tested in phase III trials.vDavid Salisbury, an associate fellow of the global health program at Chatham House said another area of confusion is that the press release pooled results from the two groups to reach an average of 70% efficacy. “You’ve taken two studies for which different doses were used and come up with a composite that doesn’t represent either of the doses,″ Salisbury told the AP. “I think many people are having trouble with that.″ 

Researchers say a smaller first dose could be more effective because you need just the right amount to get a good immune response. Some have criticised AstraZeneca and Oxford for a lack of transparency in the results release.  "Astrazeneca/Oxford get a poor grade for transparency and rigor when it comes to the vaccine trial results they have reported. This is not like Pfizer or Moderna where we had the protocols in advance and a pre-specified primary analysis was reported," Natalie Dean, an assistant professor of biostatistics at the University of Florida. "If they seek to get the half-dose approved, they should wait until they have a compelling result. Otherwise, we can land in 'evidence limbo.'"  More detailed results from the trials are expected to be provided to regulators who will decide whether to authorise the vaccine. Moncef Slaoui, who leads the US coronavirus vaccine program, said in a call with reporters that US officials are trying to determine what immune response the vaccine produced.  They may decide to modify the AstraZeneca study in the US to include a half dose: “But we want it to be based on data and science,” he said. Euronews has reached out to AstraZeneca for comment.

UK drug company says that while further research is needed, it did not expect it to delay regulatory approval in Europe.  AstraZeneca might have to run an additional global trial to assess the efficacy of its COVID-19 vaccine, after concerns were raised about the effectiveness of its jab. The British company’s chief executive Pascal Soriot was quoted as saying in a Bloomberg News report on Thursday that an additional study would be run to evaluate a lower dosage that performed better than a full amount in AstraZeneca’s studies. “Now that we’ve found what looks like a better efficacy we have to validate this, so we need to do an additional study,” Soriot was quoted as saying. Soriot said it would probably be another “international study, but this one could be faster because we know the efficacy is high, so we need a smaller number of patients”. The news comes as AstraZeneca, and its partner the University of Oxford, has faced questions about its success rate that some experts said could hinder its chances of getting speedy approval by United States and European Union’s regulators.

Several scientists have raised doubts about the robustness of results released on Monday showing the experimental vaccine was 90 percent effective in a sub-group of trial participants who, by error initially, received a half-dose followed by a full dose.  Soriot said he did not expect the additional trial to delay United Kingdom and European regulatory approvals. Clearance from the US Food and Drug Administration (FDA) may take longer though because the agency is unlikely to approve the vaccine based on studies carried out elsewhere, especially given the questions about the results, he said. Authorisation in some countries is still expected before the end of the year, he added. AstraZeneca research chief Mene Pangalos told Reuters on Monday that researchers had stumbled upon the half-dose regime by accident, saying a sub-group of the trial was given a smaller initial dose by mistake. Earlier he had said that the firm would start discussions with the FDA to change the design of its experimental COVID-19 vaccine trial to add the more-effective dosage regime...